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Modulation of the mRNA-binding protein HuR as a novel reversal mechanism of epirubicin-triggered multidrug resistance in colorectal cancer cells.
PLoS One. 2017; 12(10):e0185625.Plos

Abstract

HuR (ELAVL1), a RNA-binding protein, plays a key role in posttranscriptional regulation of multidrug resistance (MDR)-related genes. Among various HuR-regulated oncogenic transcripts, the activation of galectin-3/β-catenin survival pathway is critical to induce transcription of cyclin D1, P-glycoprotein (P-gp) and/or multidrug resistance-associated proteins (MRPs). In this study, we aim to elucidate the HuR-regulating pathways related to epirubicin-mediated resistance in human colorectal carcinoma cells. The effects and mechanisms of epirubicin treatment on the expressions of upstream survival signals (e.g., β-catenin) and downstream MDR transporters (e.g., P-gp) and anti-apoptotic pathways (e.g., Bcl-2) were assessed with or without HuR knockdown (siHuR) or overexpression (overHuR; ectopic HuR or pcDNA3/HA-HuR). Our results showed that siHuR decreased transcriptional expressions of galectin-3, β-catenin, cyclin D1, Bcl-2, P-gp, MRP1, and MRP2 in epirubicin-treated colon cancer cells. Consistently, the co-treatment of epirubicin and siHuR diminished the expressions of galectin-3, β-catenin, c-Myc, P-gp and MRP1. HuR silencing enhanced the intracellular accumulation of epirubicin in colon cancer cells. On the other hand, overHuR abolished such effects. Furthermore, siHuR significantly intensified epirubicin-mediated apoptosis via increasing reactive oxygen species and thus promoted the cytotoxic effect of epirubicin. The combined treatments of siHuR and epirubicin significantly reduced the expression of Bcl-2, but increased the expression of Bax, as well as activity and expression levels of caspase-3 and -9. In contrast, overHuR abrogated these effects. Our findings provide insight into the mechanisms by which siHuR potentiated epirubicin-induced cytotoxicity via inhibiting galectin-3/β-catenin signaling, suppressing MDR transporters and provoking apoptosis. To our best knowledge, this is an innovative investigation linking the post-transcriptional control by HuR silencing to survival signaling repression, efflux transporter reversal and apoptosis induction. Our study thus provides a powerful regimen for circumventing MDR in colon cancer cells.

Authors+Show Affiliations

Department of Biological Sciences and Technology, National University of Tainan, Tainan, Taiwan.Department of Biological Sciences and Technology, National University of Tainan, Tainan, Taiwan.Institute of Bioinformatics and Biosignaling Transduction, National Cheng Kung University, Tainan, Taiwan.Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28968471

Citation

Lin, Guan-Liang, et al. "Modulation of the mRNA-binding Protein HuR as a Novel Reversal Mechanism of Epirubicin-triggered Multidrug Resistance in Colorectal Cancer Cells." PloS One, vol. 12, no. 10, 2017, pp. e0185625.
Lin GL, Ting HJ, Tseng TC, et al. Modulation of the mRNA-binding protein HuR as a novel reversal mechanism of epirubicin-triggered multidrug resistance in colorectal cancer cells. PLoS One. 2017;12(10):e0185625.
Lin, G. L., Ting, H. J., Tseng, T. C., Juang, V., & Lo, Y. L. (2017). Modulation of the mRNA-binding protein HuR as a novel reversal mechanism of epirubicin-triggered multidrug resistance in colorectal cancer cells. PloS One, 12(10), e0185625. https://doi.org/10.1371/journal.pone.0185625
Lin GL, et al. Modulation of the mRNA-binding Protein HuR as a Novel Reversal Mechanism of Epirubicin-triggered Multidrug Resistance in Colorectal Cancer Cells. PLoS One. 2017;12(10):e0185625. PubMed PMID: 28968471.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulation of the mRNA-binding protein HuR as a novel reversal mechanism of epirubicin-triggered multidrug resistance in colorectal cancer cells. AU - Lin,Guan-Liang, AU - Ting,Huei-Ju, AU - Tseng,Ta-Chien, AU - Juang,Vivian, AU - Lo,Yu-Li, Y1 - 2017/10/02/ PY - 2017/05/01/received PY - 2017/09/15/accepted PY - 2017/10/3/entrez PY - 2017/10/3/pubmed PY - 2017/11/1/medline SP - e0185625 EP - e0185625 JF - PloS one JO - PLoS One VL - 12 IS - 10 N2 - HuR (ELAVL1), a RNA-binding protein, plays a key role in posttranscriptional regulation of multidrug resistance (MDR)-related genes. Among various HuR-regulated oncogenic transcripts, the activation of galectin-3/β-catenin survival pathway is critical to induce transcription of cyclin D1, P-glycoprotein (P-gp) and/or multidrug resistance-associated proteins (MRPs). In this study, we aim to elucidate the HuR-regulating pathways related to epirubicin-mediated resistance in human colorectal carcinoma cells. The effects and mechanisms of epirubicin treatment on the expressions of upstream survival signals (e.g., β-catenin) and downstream MDR transporters (e.g., P-gp) and anti-apoptotic pathways (e.g., Bcl-2) were assessed with or without HuR knockdown (siHuR) or overexpression (overHuR; ectopic HuR or pcDNA3/HA-HuR). Our results showed that siHuR decreased transcriptional expressions of galectin-3, β-catenin, cyclin D1, Bcl-2, P-gp, MRP1, and MRP2 in epirubicin-treated colon cancer cells. Consistently, the co-treatment of epirubicin and siHuR diminished the expressions of galectin-3, β-catenin, c-Myc, P-gp and MRP1. HuR silencing enhanced the intracellular accumulation of epirubicin in colon cancer cells. On the other hand, overHuR abolished such effects. Furthermore, siHuR significantly intensified epirubicin-mediated apoptosis via increasing reactive oxygen species and thus promoted the cytotoxic effect of epirubicin. The combined treatments of siHuR and epirubicin significantly reduced the expression of Bcl-2, but increased the expression of Bax, as well as activity and expression levels of caspase-3 and -9. In contrast, overHuR abrogated these effects. Our findings provide insight into the mechanisms by which siHuR potentiated epirubicin-induced cytotoxicity via inhibiting galectin-3/β-catenin signaling, suppressing MDR transporters and provoking apoptosis. To our best knowledge, this is an innovative investigation linking the post-transcriptional control by HuR silencing to survival signaling repression, efflux transporter reversal and apoptosis induction. Our study thus provides a powerful regimen for circumventing MDR in colon cancer cells. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/28968471/Modulation_of_the_mRNA_binding_protein_HuR_as_a_novel_reversal_mechanism_of_epirubicin_triggered_multidrug_resistance_in_colorectal_cancer_cells_ L2 - https://dx.plos.org/10.1371/journal.pone.0185625 DB - PRIME DP - Unbound Medicine ER -